Rheumatoid arthritis (RA) is a common chronic inflammatory arthritis that affects about 1% of adults worldwide, with a female predominance and a peak onset in the fourth decade of life (See, Firestein, “Rheumatoid Arthritis,” in Scientific American Medicine, 2000; and Cohen, “Systemic Autoimmunity,” in Paul (ed.) Fundamental Immunology, Lippincott-Raven Publishers: Philadelphia, pp. 1067-1088, 1999). Intense inflammation occurs in synovial joints, with infiltration of the synovial membrane by mononuclear phagocytes, lymphocytes and neutrophils, causing significant joint pain. In addition, RA patients generally develop loss of cartilage and bone around joints, which leads to a loss of mobility.
Although the cause of RA has not been precisely defined, various characteristics of the disease are indicative of an autoimmune component to RA etiology. In particular, macrophage and fibroblast-derived cytokines are abundantly expressed in rheumatoid joints (Firestein et al., J Immunol, 144:3347, 1994). Tumor necrosis factor alpha (TNFα) and interleukin-1 (IL-1) appear to be the major pathogenic factors, in that both can induce synoviocyte proliferation, collagenase production, and prostaglandin release, while overexpression can induce arthritis in animal models (Firestein, supra, 2000). IL-18 is also present in RA joints and can directly activate macrophages to produce proinflammatory cytokines (Gracie et al., J Clin Invest, 104:1393, 1999).
Current RA therapies are directed to analgesia, control of inflammation, and alteration of the disease course. More aggressive treatment approaches are now frequently adopted, with RA patients rapidly requiring a switch from non-steroidal anti-inflammatory drugs (NSAIDs) to a second line reagent such as methotrexate. Unfortunately, methotrexate alone does not adequately control RA in most patients, causing physicians to select either add-on therapy or a series of single agents (Firestein, supra, 2000), for example leflunomide, sulfasalazine, or a TNF inhibitor. TNF-inhibitors that have been used with some success to treat RA include TNF-reactive monoclonal antibodies (infliximab/REMICADE and adalimumab/HUMIRA) and a soluble TNF-receptor/immunoglobulin fusion protein (etanercept/ENBREL). However, it is desirable to provide clinicians with additional therapies to use alone or as cocktails to halt the progression of this debilitating disease.